tbuckley/cabot-search huggingface dataset:
Clostridium epsilon toxin is excessive in multiple sclerosis and provokes multifocal lesions in mouse models
Authors: Anthony T. Reder
Journal: Journal of Clinical Investigation (2023)

Multiple sclerosis (MS) is an inflammatory disease of the CNS. In this issue of the JCI, Ma and Sannino et al. show that two strains of intestinal Clostridium perfringens, known to produce epsilon toxin (ETX), were frequently found in patients with MS. Tiny amounts of this toxin added to immunization with myelin antigens provoked MS-like brain lesions in mice. The distribution of these lesions was diffuse, as in MS, in contrast to the spinal cord-restricted lesions of most animal models. ETX bound to endothelial cells of the CNS to enhance immune cell trafficking through the blood-brain barrier into inflammatory brain lessons. ETX also binds to human, but not murine, white blood cells, perhaps altering immune responses. Barrier disruption and changes in immunity due to the toxin could alter the benefits of immune-modulatory MS therapies and are likely to interact with the complex genetics and environmental influences seen in MS.
An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA
Authors: Kai Rejeski, Raffaella Greco, Francesco Onida, Isabel Sánchez-Ortega, Chiara Bonini, Anna Sureda, John G. Gribben, Ibrahim Yakoub-Agha, Marion Subklewe
Journal: HemaSphere (2023)

Hematological toxicity represents the most common grade ≥3 toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. To inform the forthcoming European Hematology Association/European Society for Blood and Marrow Transplantation (EHA/EBMT) guidelines on the management of "immune effector cell-associated hematotoxicity" (ICAHT), we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term, and (4) long-term management of ICAHT. There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile. Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin, 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. In case of prolonged thrombocytopenia, most survey participants favored thrombopoietin agonists (86%). Conversely, autologous hematopoietic cell boosts represented the preferred choice for neutropenia (63%), although they were frequently not available and no consensus was reached regarding the optimal trigger point. These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines.
Mass spectrometric simultaneous quantification of tau species in plasma shows differential associations with amyloid and tau pathologies
Authors: Laia Montoliu-Gaya, Andréa L. Benedet, Cécile Tissot, Agathe Vrillon, Nicholas J. Ashton, Wagner S. Brum, Juan Lantero-Rodriguez, Jenna Stevenson, Johanna Nilsson, Mathias Sauer, Nesrine Rahmouni, Gunnar Brinkmalm, Firoza Z. Lussier, Tharick A. Pascoal, Ingmar Skoog, Silke Kern, Henrik Zetterberg, Claire Paquet, Johan Gobom, Pedro Rosa-Neto, Kaj Blennow
Journal: Nature Aging (2023)

Abstract Blood phosphorylated tau (p-tau) biomarkers, at differing sites, demonstrate high accuracy to detect Alzheimerʼs disease (AD). However, knowledge on the optimal marker for disease identification across the AD continuum and the link to pathology is limited. This is partly due to heterogeneity in analytical methods. In this study, we employed an immunoprecipitation mass spectrometry method to simultaneously quantify six phosphorylated (p-tau181, p-tau199, p-tau202, p-tau205, p-tau217 and p-tau231) and two non-phosphorylated plasma tau peptides in a total of 214 participants from the Paris Lariboisière and Translational Biomarkers of Aging and Dementia cohorts. Our results indicate that p-tau217, p-tau231 and p-tau205 are the plasma tau forms that best reflect AD-related brain changes, although with distinct emergences along the disease course and correlations with AD features—amyloid and tau. These findings support the differential association of blood p-tau variants with AD pathology, and our method offers a potential tool for disease staging in clinical trials.
Popular Dietary Patterns: Alignment With American Heart Association 2021 Dietary Guidance: A Scientific Statement From the American Heart Association
Authors: Christopher D. Gardner, Maya K. Vadiveloo, Kristina S. Petersen, Cheryl A.M. Anderson, Sparkle Springfield, Linda Van Horn, Amit Khera, Cindy Lamendola, Shawyntee M. Mayo, Joshua J. Joseph
Journal: Circulation (2023)

The evolution of dietary guidelines from isolated nutrients to broader dietary pattern recommendations results from growing knowledge of the synergy between nutrients and their food sources as they influence health. Macronutrient and micronutrient needs can be met by consuming various dietary patterns, but guidance is often required to facilitate population-wide adherence to wise food choices to achieve a healthy dietary pattern. This is particularly true in this era with the proliferation of nutrition misinformation and misplaced emphasis. In 2021, the American Heart Association issued a scientific statement outlining key principles of a heart-healthy dietary pattern that could be operationalized in various ways. The objective of this scientific statement is to assess alignment of commonly practiced US dietary patterns with the recently published American Heart Association criteria, to determine clinical and cultural factors that affect long-term adherence, and to propose approaches for adoption of healthy dietary patterns. This scientific statement is intended to serve as a tool for clinicians and consumers to evaluate whether these popular dietary pattern(s) promote cardiometabolic health and suggests factors to consider when adopting any pattern to improve alignment with the 2021 American Heart Association Dietary Guidance. Numerous patterns strongly aligned with 2021 American Heart Association Dietary Guidance (ie, Mediterranean, DASH [Dietary Approaches to Stop Hypertension], pescetarian, vegetarian) can be adapted to reflect personal and cultural preferences and budgetary constraints. Thus, optimal cardiovascular health would be best supported by developing a food environment that supports adherence to these patterns wherever food is prepared or consumed.
Additive manufacturing of sustainable biomaterials for biomedical applications
Authors: Zia Ullah Arif, Muhammad Yasir Khalid, Reza Noroozi, Mokarram Hossain, HaoTian Harvey Shi, Ali Tariq, Seeram Ramakrishna, Rehan Umer
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Biopolymers are promising environmentally benign materials applicable in multifarious applications. They are especially favorable in implantable biomedical devices thanks to their excellent unique properties, including bioactivity, renewability, bioresorbability, biocompatibility, biodegradability and hydrophilicity. Additive manufacturing (AM) is a flexible and intricate manufacturing technology, which is widely used to fabricate biopolymer-based customized products and structures for advanced healthcare systems. Three-dimensional (3D) printing of these sustainable materials is applied in functional clinical settings including wound dressing, drug delivery systems, medical implants and tissue engineering. The present review highlights recent advancements in different types of biopolymers, such as proteins and polysaccharides, which are employed to develop different biomedical products by using extrusion, vat polymerization, laser and inkjet 3D printing techniques in addition to normal bioprinting and four-dimensional (4D) bioprinting techniques. This review also incorporates the influence of nanoparticles on the biological and mechanical performances of 3D-printed tissue scaffolds. This work also addresses current challenges as well as future developments of environmentally friendly polymeric materials manufactured through the AM techniques. Ideally, there is a need for more focused research on the adequate blending of these biodegradable biopolymers for achieving useful results in targeted biomedical areas. We envision that biopolymer-based 3D-printed composites have the potential to revolutionize the biomedical sector in the near future.
Synergistic cancer immunotherapy utilizing programmed Salmonella typhimurium secreting heterologous flagellin B conjugated to interleukin-15 proteins
Authors: Ying Zhang, Wenzhi Tan, Rukhsora D. Sultonova, Dinh-Huy Nguyen, Jin Hai Zheng, Sung-Hwan You, Joon Haeng Rhee, So-young Kim, Koemchhoy Khim, Yeongjin Hong, Jung-Joon Min
Journal: Biomaterials (2023)

The use of appropriately designed immunotherapeutic bacteria is an appealing approach to tumor therapy because the bacteria specifically target tumor tissue and deliver therapeutic payloads. The present study describes the engineering of an attenuated strain of Salmonella typhimurium deficient in ppGpp biosynthesis (SAM) that could secrete Vibrio vulnificus flagellin B (FlaB) conjugated to human (hIL15/FlaB) and mouse (mIL15/FlaB) interleukin-15 proteins in the presence of L-arabinose (L-ara). These strains, named SAMphIF and SAMpmIF, respectively, secreted fusion proteins that retained bioactivity of both FlaB and IL15. SAMphIF and SAMpmIF inhibited the growth of MC38 and CT26 subcutaneous (sc) tumors in mice and increased mouse survival rate more efficiently than SAM expressing FlaB alone (SAMpFlaB) or IL15 alone (SAMpmIL15 and SAMphIL15), although SAMpmIF had slightly greater antitumor activity than SAMphIF. The mice treated with these bacteria showed enhanced macrophage phenotype shift, from M2-like to M1-like, as well as greater proliferation and activation of CD4+ T, CD8+ T, NK, and NKT cells in tumor tissues. After tumor eradication by these bacteria, ≥50% of the mice show no evidence of tumor recurrence upon rechallenge with the same tumor cells, indicating that they had acquired long-term immune memory. Treatment of mice of 4T1 and B16F10 highly malignant sc tumors with a combination of these bacteria and an immune checkpoint inhibitor, anti-PD-L1 antibody, significantly suppressed tumor metastasis and increased mouse survival rate. Taken together, these findings suggest that SAM secreting IL15/FlaB is a novel therapeutic candidate for bacterial-mediated cancer immunotherapy and that its antitumor activity is enhanced by combination with anti-PD-L1 antibody.
Methotrexate suppresses psoriatic skin inflammation by inhibiting muropeptide transporter SLC46A2 activity
Authors: Ravi Bharadwaj, Christina F. Lusi, Siavash Mashayekh, Abhinit Nagar, Malireddi Subbarao, Griffin I. Kane, Kimberly A. Wodzanowski, Ashley R. Brown, Kendi Okuda, Amanda Monahan, Donggi Paik, Anubhab Nandy, Madison V. Anonick, William E. Goldman, Thirumala-Devi Kanneganti, Megan H. Orzalli, Catherine Leimkuhler Grimes, Prabhani U. Atukorale, Neal Silverman
Journal: Immunity (2023)

Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here, we focused on Slc46a2, which was highly expressed in mammalian epidermal keratinocytes, and showed that it was critical for the delivery of diaminopimelic acid (DAP)-muropeptides and activation of NOD1 in keratinocytes, whereas the related transporter Slc46a3 was critical for delivering the NOD2 ligand MDP to keratinocytes. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, whereas methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively, these studies define SLC46A2 as a transporter of NOD1-activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.
A recombinant spike‐XBB.1.5 protein vaccine induces broad‐spectrum immune responses against XBB.1.5‐included Omicron variants of SARS‐CoV‐2
Authors: Cai He, Aqu Alu, Hong Lei, Jingyun Yang, Weiqi Hong, Xiangrong Song, Jiong Li, Li Yang, Wei Wang, Guobo Shen, Guangwen Lu, Xiawei Wei
Journal: MedComm (2023)

The XBB.1.5 subvariant has drawn great attention owing to its exceptionality in immune evasion and transmissibility. Therefore, it is essential to develop a universally protective coronavirus disease 2019 vaccine against various strains of Omicron, especially XBB.1.5. In this study, we evaluated and compared the immune responses induced by six different spike protein vaccines targeting the ancestral or various Omicron strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice. We found that spike-wild-type immunization induced high titers of neutralizing antibodies (NAbs) against ancestral SARS-CoV-2. However, its activity in neutralizing Omicron subvariants decreased sharply as the number of mutations in receptor-binding domain (RBD) of these viruses increased. Spike-BA.5, spike-BF.7, and spike-BQ.1.1 vaccines induced strong NAbs against BA.5, BF.7, BQ.1, and BQ.1.1 viruses but were poor in protecting against XBB and XBB.1.5, which have more RBD mutations. In sharp contrast, spike-XBB.1.5 vaccination can activate strong and broadly protective immune responses against XBB.1.5 and other common subvariants of Omicron. By performing correlation analysis, we found that the NAbs titers were negatively correlated with the number of RBD mutations in the Omicron subvariants. Vaccines with more RBD mutations can effectively overcome the immune resistance caused by the accumulation of RBD mutations, making spike-XBB.1.5 the most promising vaccine candidate against universal Omicron variants.
Advanced therapy medicinal products in China: Regulation and development
Authors: Jiaqi Lu, Longchang Xu, Wei Wei, Wu He
Journal: MedComm (2023)

Advanced therapy medicinal products (ATMPs) have shown dramatic efficacy in addressing serious diseases over the past decade. With the acceleration and deepening of China's drug regulatory reforms, the country sees a continuous introduction of policies that encourage drug innovation. The capacity and efficiency of the Center for Drug Evaluation (CDE), National Medical Products Administration have significantly improved, where substantial resources have been allocated to ATMPs with major innovations and outstanding clinical values that satisfy urgent clinical needs. These changes have greatly stimulated the research and development of biological products in China, ushering in a period of explosive growth in the number of investigational new drug (IND) applications of ATMPs. Here, we described China's ATMP regulatory framework and analyzed data on IND applications for ATMPs submitted to CDE. The data show that China's ATMP industry is expanding dramatically, but lagging behind in terms of the innovative targets and the coverage of indications. However, in recent years, the diversity of product types, targets, and indications is growing. We discussed challenges and opportunities in ATMP regulation. Risk-based regulation and cross-discipline collaborations are encouraged to promote more ATMPs toward market authorization in China.
Reply to Binghao Zhao, Ruidong Zhang, and Jiaming Wu’s Letter to the Editor re: Ana Cavillon, Damien Pouessel, Nadine Houédé, et al. Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2023.02.011
Authors: Ana Cavillon, Raphael Porcher, Thomas Filleron
Journal: European Urology (2023)
Immune mechanisms of toxicity from checkpoint inhibitors
Authors: S. Jennifer Wang, Stephanie K. Dougan, Michael Dougan
Journal: Trends in cancer (2023)

Immunotherapy has changed the treatment landscape for cancer over the past decade. Inhibitors of the immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset of patients with metastatic disease. However, these treatments can be limited by inflammatory toxicities that can affect any organ system in the body and in some cases can be life threatening. Considerable progress has been made in understanding the drivers of these toxicities as well as effective management strategies. Further research into understanding the molecular and cellular mechanisms that drive toxicity will enable better prediction of toxicity and development of optimized therapies for these toxicities that avoid interfering with antitumor immunity. In this review, we discuss our current understanding of the inflammatory toxicities from immune checkpoint inhibitors (ICIs) and propose optimal treatment strategies for these toxicities.
Lung Cancer in Never Smokers: A Review
Authors: Janakiraman Subramanian, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2007)

Lung cancer is the leading cause of cancer-related death in the United States. Although tobacco smoking accounts for the majority of lung cancer, approximately 10% of patients with lung cancer in the United States are lifelong never smokers. Lung cancer in the never smokers (LCINS) affects women disproportionately more often than men. Only limited data are available on the etiopathogenesis, molecular abnormalities, and prognosis of LCINS. Several etiologic factors have been proposed for the development of LCINS, including exposure to radon, cooking fumes, asbestos, heavy metals, and environmental tobacco smoke, human papillomavirus infection, and inherited genetic susceptibility. However, the relative significance of these individual factors among different ethnic populations in the development of LCINS has not been well-characterized. Adenocarcinoma is the predominant histologic subtype reported with LCINS. Striking differences in response rates and outcomes are seen when patients with advanced non–small-cell lung cancer (NSCLC) who are lifelong never smokers are treated with epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors such as gefitinib or erlotinib compared with the outcomes with these agents in patients with tobacco-associated lung cancer. Interestingly, the activating mutations in the EGFR-TK inhibitors have been reported significantly more frequently in LCINS than in patients with tobacco-related NSCLC. This review will summarize available data on the epidemiology, risk factors, molecular genetics, management options, and outcomes of LCINS.
Physicians' Experiences with the Oregon Death with Dignity Act
Authors: Linda Ganzini, Heidi D. Nelson, Terri A. Schmidt, Dale F. Kraemer, Molly A. Delorit, Melinda A. Lee
Journal: New England Journal of Medicine (2000)

Physician-assisted suicide was legalized in Oregon in October 1997. There are data on patients who have received prescriptions for lethal medications and died after taking the medications. There is little information, however, on physicians' experiences with requests for assistance with suicide.
The Evaluation and Treatment of Seizures
Authors: Jane F. Desforges, Mark L. Scheuer, Timothy A. Pedley
Journal: New England Journal of Medicine (1990)

ONE of every 11 Americans who live to be 80 years old will have had at least one seizure. About 3 percent of the population has recurrent, unprovoked seizures (epilepsy).1 In the United States, the estimated prevalence of active epilepsy is 6.42 cases per 1000 population. On the basis of 1980 census figures, this means that at least 1.5 million people in this country have active epilepsy.2 Thus, seizures present common management problems in medical practice. The goals of treatment include minimizing both the risk of recurrence of seizures and the deleterious side effects sometimes associated with antiepileptic drug therapy, . . .
A Comparison of Inhaled Fluticasone and Oral Prednisone for Children with Severe Acute Asthma
Authors: Suzanne Schuh, Joseph Reisman, Mohammed Alshehri, Annie Dupuis, Mary Corey, Rita Arseneault, Ghassan Alothman, Olwen Tennis, Gerard Canny
Journal: New England Journal of Medicine (2000)

Inhaled corticosteroids are effective in the treatment of children with asthma. It is uncertain how inhaled corticosteroids compare with oral corticosteroids in the management of severe acute disease.
Adverse Subjective Experience With Antipsychotics and Its Relationship to Striatal and Extrastriatal D <sub>2</sub> Receptors: a PET Study in Schizophrenia
Authors: Romina Mizrahi, Pablo Rusjan, Ofer Agid, Ariel Graff, David C. Mamo, Robert B. Zipursky, Shitij Kapur
Journal: American Journal of Psychiatry (2007)

OBJECTIVES: Antipsychotic medications improve psychosis but often induce a state of dysphoria in patients. Blockade of the dopamine D 2 receptors, which is thought to mediate their efficacy, has also been implicated in producing this adverse subjective experience. The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D 2 receptor binding potential and occupancy values and adverse subjective experience. Method: Patients with recent-onset psychosis (N=12) were randomly assigned to low or high doses of olanzapine or risperidone. Subjective experiences, motor side effects, and striatal and extrastriatal dopamine D 2 receptors (determined with ([ 11 C]raclopride and [ 11 C]FLB 457 PET scans, respectively) were evaluated after 2 weeks of continuous antipsychotic treatment. Results: Higher dopamine D 2 receptor occupancy and binding potentials in the striatal (dorsal and ventral), temporal, and insular regions were associated with subjective experience. The finding was confirmed with two convergent methods of analysis (region-of-interest and voxel-based statistics), and the same relationship was observed using two different dopamine receptor measures (observed binding potential values and age- and sex-corrected occupancy values). Conclusions: Higher D 2 receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D 2 ) mechanisms may be critical in improving the treatment of psychosis.
The Irritable Bowel Syndrome
Authors: Brenda J. Horwitz, Robert S. Fisher
Journal: New England Journal of Medicine (2001)

In 1849, Cumming1 said of the irritable bowel syndrome, "The bowels are at one time constipated, another lax, in the same person. How the disease has two such different symptoms I do not profess to explain." Over the years, the unexplained gastrointestinal symptoms of the irritable bowel syndrome have been described in various terms, including mucous colitis, spastic colitis, nervous colon, and irritable colon. The irritable bowel syndrome and nonulcer dyspepsia are the most common functional gastrointestinal disorders.The irritable bowel syndrome is defined on the basis of the recently modified Rome criteria as the presence for at least 12 . . .